This research will investigate a new approach to the stereoselective synthesis of complex molecular frameworks. The result will be efficient access to a number of polycyclic molecules of biological importance, allowing, in some cases, enantioselective syntheses of complex scaffolds for the first time. The strategy will involve metal-catalyzed cyclopropanations of electron-rich alkenes with ?-substituted ?-diazo esters to generate donor-acceptor cyclopropane (DAC) rings that are geminally substituted with both an electron-stabilizing group and a latent nucleophile. Activation with a Lewis acid is expected to induce ring opening to form a zwitterion, and the stabilized carbocation will be trapped by intramolecular nucleophilic addition, resulting in a net annulation of the alkene moiety. These DAC intermediates will serve as templates for the synthesis of a number of natural products that show promise as therapeutic agents. We will begin by preparing cyclopropanes that are geminally substituted with ester and diethoxyphosphoryl groups and study their rearrangement to ?-phosphono-?-lactones. Applied to a chiral 2H-chromene substrate, this method will be used to complete the first enantioselective synthesis of isochamaejasmine. This biflavonoid has been shown to alter several cell-signaling pathways, and has been found to be active against several tumor cell lines including human myeloid leukemia cells. We will then expand this strategy to the formation of carbocycles by preparing cyclopropanes that contain an ester geminally substituted with a carbon-based latent nucleophile in the form of an electron-rich alkene. Following zwitterion formation, the electron-rich alkene will act as the internal nucleophile. Among the nucleophiles studied will be alkoxy-substituted benzenes, leading to the enantioselective synthesis of a known cytotoxic benzopyran, and indoles, potentially providing an efficient route to the tetracyclic core of dragmacidin E. Dragmacidin E is an inhibitor of serine-threonine protein phosphatase, and compounds in this class have also shown antitumor activity. The ultimate goals of this research are to advance the field of synthesis and impact the field of cancer drug therapy by identifying potential lead compounds. Synthetic routes to the aforementioned targets will facilitate their comprehensive clinical analysis. PUBLIC HEALTH RELEVANCE: This project proposes to develop new synthetic strategies for preparing several medicinally-active natural products that show promise as therapeutic agents. The list includes compounds active against myeloid leukemia, diabetic neuropathy, and tuberculosis. Bio-identical laboratory syntheses of these natural products will facilitate their comprehensive clinical analysis.